As noted above, in response to the concern about the appropriate diagnosis for children with chronic, severe irritability, we defined a group of children whom we described as having severe mood dysregulation (SMD). These children have extremely severe irritability and symptoms of hyperarousal (the latter being similar to those seen in attention deficit hyperactivity disorder (ADHD)) and, although they frequently receive the diagnosis of bipolar disorder (BD), they do not indeed meet diagnostic criteria for BD. Since the inception of this project, approximately 200 youth with SMD have been recruited into the project. Approximately 20 new patients were recruited this year. It is very important to note that these youth with SMD suffer very severe psychiatric impairment, and indeed are as ill as are youth with BD in terms of number of medications prescribed, number of psychiatric hospitalizations, and standardized measures of function. Also as noted above, in previous years we demonstrated differences between youth with SMD and those with BD in terms of clinical course, family history, and the brain mechanisms associated with behavioral problems. This year we gathered more data to support the conclusion that, while youth with SMD and those with BD both have severe mood disorders, the two groups differ in the nature of their brain dysfunction. In prior work, we demonstrated that youth with BD or SMD, but not those with other psychiatric illnesses, have deficits in face emotion labeling. This year we used eye tracking technology to determine whether abnormalities in the facial feature at which subjects look is associated with face labeling deficits. Whereas we found clear evidence that youth with BD look at noses more, and eyes less, than do healthy subjects, the findings in SMD were equivocal. That is, subjects with SMD did not differ from either healthy subjects or those with BD in their eye gaze patterns, suggesting that further study is warranted. We also have continued to accrue data regarding the extent to which amygdala activation differs among healthy subjects, those with BD, and those with SMD when viewing emotional faces. In one study which is in press, both patient populations failed to modulate amygdala activity appropriately while viewing angry faces. Specifically, healthy subjects showed increased amygdala activity as the amount of anger on a face increased, while neither of the patient samples did so. This failure to modulate amygdala activity in response to subtle changes in face emotion might be associated with the deficit in face emotion labeling that patients exhibit. In another manuscript that has been submitted for publication, we found that youth with SMD and those with BD both showed amygdala hyperactivation (relative to healthy subjects) when viewing angry or fearful faces. However, activity differed between the two patient populations in other brain regions. Specifically, compared to both healthy subjects and those with BD, youth with SMD have decreased insula and parietal activation when viewing fearful faces. One of the central clinical issues for youth with severe irritability is anxiety. This raises issues about the extent to which the neural circuitry mediating irritability and anxiety overlap, and the extent to which treatments that are effective for anxiety (e.g., serotonergic reuptake inhibitors) will help children whose primary symptom is irritability. One psychological deficit that has been demonstrated repeatedly in both children and adults with anxiety is the presence of a threat bias i.e., the tendency to attend differentially to angry or fearful faces. In data that will be submitted for publication soon, we demonstrate that youth with SMD show a threat bias, compared to healthy youth. This suggests the possibility of shared neural mechanisms between irritability and anxiety, with potential treatment implications. Given the central role that excessive responses to frustration play in the symptomatology of SMD, additional neuroimaging studies focus very directly on the brain dysfunction associated with frustration in SMD. Specifically, this year we completed one such study and have submitted the manuscript for publication. We found that, when frustrated, youth with SMD had more difficulty than healthy subjects regulating their attention. In addition, when frustrated and receiving negative feedback, compared to healthy subjects, those with SMD exhibited decreased activation in the amygdala, striatum, and parietal regions. On the other hand, when subjects were frustrated and received positive feedback, there was no difference in brain activity between healthy subjects and those with SMD. These findings indicate that in response to negative feedback received in the context of frustration, youth with severe, chronic irritability show abnormally reduced activation in regions implicated in emotion, attention, and reward processing. This raises the possibility that a treatment aimed at training irritable youth to control their attention more effectively when frustrated might have therapeutic effects, although considerably more research needs to be conducted to confirm the feasibility and appropriateness of this approach. The fact that youth with SMD share many symptoms with youth with attention deficit hyperactivity disorder (ADHD), as well as an increasing emphasis on dimensional, rather than categorical, classification in psychiatry, is an important impetus for a new research approach that we began to adopt this year and will continue in the coming year. Consistent with the Research Domain Criteria initiative of the NIMH, we have adopted a dimensional approach to irritability, studying not just youth with SMD and healthy youth, but also youth with ADHD and different levels of irritability. This approach allows us to adopt a dimensional approach to irritability while also controlling for the fact that SMD youth have ADHD symptoms. We are currently conducting fMRI studies comparing brain function among healthy subjects, those with SMD, and those with ADHD and differing levels of irritability. Finally, from a public health perspective, it is essential to determine whether the distinction between SMD and BD, which is evident in terms of clinical course, family history, and neural circuitry, is also associated with between-group differences in treatment response. In previous work, we found that lithium was not effective in the treatment of SMD. Last year, we began a double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor antidepressant) plus stimulant is more effective than placebo plus stimulant in the treatment of SMD. Thus far, we have randomized approximately 25 children into the trial, and youth are tolerating the experimental treatment well.